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Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity
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Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity
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Journal Article
Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity
2020
Overview
Small molecules that selectively kill senescent cells (SCs), termed senolytics, have the potential to prevent and treat various age-related diseases and extend healthspan. The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity. Here, we report the use of proteolysis-targeting chimera (PROTAC) technology to reduce the platelet toxicity of navitoclax (also known as ABT263), a Bcl-2 and Bcl-xl dual inhibitor, by converting it into PZ15227 (PZ), a Bcl-xl PROTAC, which targets Bcl-xl to the cereblon (CRBN) E3 ligase for degradation. Compared to ABT263, PZ is less toxic to platelets, but equally or slightly more potent against SCs because CRBN is poorly expressed in platelets. PZ effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia. With further improvement, Bcl-xl PROTACs have the potential to become safer and more potent senolytic agents than Bcl-xl inhibitors.
Senolytics have the potential to extend healthspan by selectively killing senescent cells (SCs), but senolytics that target Bcl-xl may cause platelet toxicity. Here, the authors generated a Bcl-xl proteolysis-targeting chimera (PROTAC) senolytic, which effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/2
/ 631/154
/ 96/31
/ Adaptor Proteins, Signal Transducing - metabolism
/ Age
/ Aniline Compounds - chemistry
/ Aniline Compounds - pharmacology
/ Animals
/ bcl-X Protein - antagonists & inhibitors
/ Blood Platelets - drug effects
/ Cancer
/ Cellular Senescence - drug effects
/ Female
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Ligands
/ Male
/ Mice
/ Pharmacy
/ Proteins
/ Science
/ Toxicity
